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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the invention provides compounds; pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
• PPAR Peroxisome Proliferator-Activated Receptor
• Peroxisome Proliferator Activated Receptors are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Certain PPARs are associated with a number of disease states including dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease. Accordingly, molecules that modulate the activity of PPARs are useful as therapeutic agents in the treatment of such diseases. SUMMARY OF THE INVENTION
• the present invention provides compounds of Formula I:
• n is selected from 0, 1 and 2;
• Ri is -OCRi 1R 12 XCO2R 1 3; wherein X is selected from a bond and Ci- 4 alkylene; and Rn and R 12 are independently selected from hydrogen, C M alkyl and Ci- 4 alkoxy; or Ri 1 and R 12 together with the carbon atom to which Ri 1 and R12 are attached form C 3 -i 2 cycloalkyl; and R1 3 is selected from hydrogen and Ci- ⁇ alkyl;
• R 2 and R 3 are independently selected from hydrogen and
• V is selected from a bond, Ci ⁇ alkylene, -C(O)NR 8 - and -XiC(O)X 2 -; wherein Xi and X2 are independently selected from a bond and C ⁇ alkylene; Rg is selected from hydrogen and C ⁇ aUcyl;
• W is a divalent radical selected from (a) and (b):
• Y is selected from O and S; and R 9 is selected from hydrogen and Ci- ⁇ alkyl;
• Z is selected from -CH2— and -C(O)-;
• R 4 is selected from hydrogen, halo, Ci ⁇ alkoxy and halo-substituted-Ci ⁇ alkoxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds.
• the present invention provides a pharmaceutical composition that contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
• the present invention provides the use of a compound of
• the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
• Alkyl as a group and as a structural element of other groups, for example
• Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
• aryl can be phenyl or naphthyl, preferably phenyl.
• Arylene means a divalent radical derived from an aryl group.
• Heteroaryl is as defined for aryl where one or more of the ring members are a heteroatom. For example.
• heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
• Ce-ioarylCo ⁇ alkyl means an aryl as described above connected via a alkylene grouping. For example, includes phenethyl, benzyl, etc.
• Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
• C 3 .iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
• Ca- ⁇ heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.
• "Halogen" (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
• T ⁇ eat refers to a method of alleviating or abating a disease and/or its attendant symptoms.
• the present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of one or more PPARs can prevent, inhibit " or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I.
• n is selected from 0 and 1; Ri is -OCR11R12XCO2R13; wherein X is selected from a bond and Ci- 4 alkylene; and Rn and R 12 are independently selected from hydrogen, Ci- 4 alkyl and Ci- 4alkoxy; or Ru and R12 together with the carbon atom to which Rn and R 1 2 are attached form Gj- ⁇ cycloalkyl; and Rn is selected from hydrogen and R2 and R 3 are independently selected from hydrogen and Ci- ⁇ alkyl; V is selected from a bond, Cj.
• Y is S; and R 9 is selected from hydrogen and Ci- ⁇ alkyl; Z is selected from -CH 2 - and -C(O)-; and R4 is selected from halo, Ci ⁇ alkyl and halo- substituted-Ci- ⁇ alkyl. - • . . .. , . , , ,
• R t is selected from -CH 2 CO 2 H, -(CH 2 ) 2 CO 2 H, -
• R 2 and R3 are independently selected from hydrogen, methyl and methoxy; and R 4 is trifluoromethyl.
• V is selected from a bond, -C(O)-, -C(O)NH-, -
• Preferred compounds of the invention are selected from: 2-(2-(4-(4-)
• Compounds of the invention modulate the activity of PPARs and, as such, are useful for treating diseases or disorders in which PPARs contributes to the pathology and/or symptomology of the disease.
• This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which PPARs contributes to the pathology and/or symptomology of the disease.
• Such compounds may therefore be employed for the treatment of prophylaxis, dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, hyper cholesteremia, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, HTV wasting syndrome, inflammation, arthritis, cancer, Alzheimer's disease, anorexia, anorexia nervosa, bulimia, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.
• prophylaxis dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, hyper cholesteremia, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, HTV wasting syndrome, inflammation, arthritis, cancer, Alzheimer's disease, anorexia, anorexia nervosa
• dyslipidemia deslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, cardiovascular diseases, hypertension, obesity, inflammation, cancer, skin disorders, EBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.
• Compounds of the invention. can also be employed to treat long term critical illness, increase muscle mass and/or muscle strength, increase lean body mass, maintain muscle strength and function in the elderly, enhance muscle endurance and muscle function, and reverse or prevent frailty in the elderly.
• US2007/002115
• the compounds of the present invention may be employed in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), and Syndrome X.
• type-1 and type-2 diabetes Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG).
• the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of the invention or a pharmaceutically acceptable salt thereof.
• a therapeutically effective amount See, "Administration and Pharmaceutical Compositions", infra
• the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
• the present invention also concerns: i) a compound of the invention or a pharmaceutically acceptable salt thereof for use as a medicament; and ii) the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating any of the diseases o ⁇ disorders described above.
• compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
• a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
• An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
• Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
• Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, orparenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
• Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
• oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,. tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants.
• diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
• lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium
• Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
• the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances.
• Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
• a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
• transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
• Matrix transdermal formulations can also be used.
• Suitable formulations for topical application, e.g., to the skin and eyes are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives, .
• This invention also concerns a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein in combination with one or more pharmaceutically acceptable carriers.
• Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
• the present invention also relates to pharmaceutical combinations, such as a combined preparation or pharmaceutical composition (fixed combination), comprising: 1) a compound of the invention as defined above or a pharmaceutical acceptable salt thereof; and 2) at least one active ingredient selected from: a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase-lB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57
• active ingredient such
• hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin; c) an anti-obesity agent or appetite regulating agent such as phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat,
• HMG-CoA 3-
• ECE inhibitors e.g. SLV306
• ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril
• angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan
• renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168
• ⁇ -adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol
• inotropic agents such as digoxin, dobutamine and milrinone
• calcium channel blockers such as digoxin, dobutamine and milrin
• a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( ⁇ N- ⁇ 5-[4-(4- methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl ⁇ -4-(3-pyridyl)-2- pyrimidine-amine ⁇ ) described in the European patent application EP-A-O 564409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- .trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide described in the patent application WO 04/005281 as example 92; and m
• Most preferred combination partners are tegaserod, imatinib, vildagliptin, metformin, a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or (7?J-l- ⁇ 4-[5-methyl-2-(4-trifluoroniethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl ⁇ - 2,3-dihydro-lH-indole-2-carboxylic acid, a sulfonylurea receptor ligand, aliskiren, valsartan, orlistat or a statin such as pitavastatin, simvastatin, fiuvastatin or pravastatin.
• a statin such as pitavastatin, simvastatin, fiuvastatin or pravastatin.
• the pharmaceutical combinations contains a therapeutically effective amount of a compound of the invention as defined above, in a combination with a therapeutically effective amount of another therapeutic agent as described above, e.g., each at an effective therapeutic dose as reported in the art.
• Combination partners (1) and (2) can be administered together, one after the other or separately in one combined unit dosage form or in two separate .unit dosage forms.
• the unit dosage form may also be a fixed combination.
• the invention concerns a pharmaceutical composition (fixed combination) comprising a therapeutically effective amount of a compound as described herein, in combination with a therapeutically effective amount of at least one active ingredient selected from the above described group a) to m), or, in each case a pharmaceutically acceptable salt thereof.
• IGM Impaired Glucose Metabolism
• ITT Impaired Glucose Tolerance
• IGF Impaired Fasting Glucose
• Such therapeutic agents include estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator, insulin, insulin derivatives and mimetics; insulin secretogogues such as the sulfonylureas, e.g., Glipizide and Amaryl; insulinotropic sulfonylurea ⁇ eceptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizers, such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors, GSK3 (glycogen synthase kinase-3) inhibitors or RXR ligands; biguanides,
• insulin secretogogues such as the sulfonylureas, e.g., Glipizide and Amaryl
• insulinotropic sulfonylurea ⁇ eceptor ligands such as meglitinides, e
• alpha-gluco_sidase.inhibitors such as acarbose
• GLP-I glucagon like peptide-1
• GLP-I analogs such as Exendin-4
• GLP-I mimetics DPPIV (dipeptidyl peptidase IV) inhibitors, e.g.
• hypolipidemic agents such as 3-hydroxy-3-methyl-gIutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fiuvastatin, dalvastatin, atorvastatin, rosuvastatin, fluindostatin and rivastatin,
• a compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
• the invention also provides for pharmaceutical combinations, e.g. a kit, comprising: a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
• a kit comprising: a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
• the kit can comprise instructions for its administration.
• co-admiriistration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
• pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
• fixed combination means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• non-fixed combination means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
• cocktail therapy e.g. the administration of 3 or more active ingredients.
• the present invention also includes processes for the preparation of compounds of the invention.
• reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
• Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in • Organic Chemistry", John Wiley and Sons'; 1991. ⁇
• Ri, R 2 and R3 are as defined for Formula I.
• Compounds of Formula 5 are prepared by reacting a compound of formula 4 with a suitable reducing agent (for example, hydrogen, and the like), a suitable solvent (for example, acetic acid, and the like) and a suitable catalyst (for example, platinum oxide, and the like). The reaction is carried out in a pressure range of about 40 to about 70 psi, a temperature range of about 0 to about 5O 0 C and takes up to about 24 hours to complete.
• a suitable reducing agent for example, hydrogen, and the like
• a suitable solvent for example, acetic acid, and the like
• a suitable catalyst for example, platinum oxide, and the like
• R2 0 is selected from NH 2 and -COOR23, -(CEb)CN, and the like (R 23 is Ci ⁇ alkyl); R 4 , Rg and n are as defined in the Summary of the Invention; and Qi is a halogen, preferably Cl, I or Br.
• Compounds of formula 8 are formed by reacting a compound of formula 6 with a compound of formula 7 in the presence of a suitable solvent (for example, acetone, ethanol, and the like). The reaction is carried out in the temperature range of about 50 to about 100 0 C and takes up to about 6 hours to complete.
• n, W, Ri, R 2 , R3 and R4 are as defined for Formula I and Qi is chloro, bromo or iodo.
• Compounds of Formula I are prepared by reacting a compound of formula 5 with a compound of formula 9 in the presence of a suitable solvent (for example, 1, 2- dichloroethane, and the like) and a suitable base (for example, diisopropylethylamine, and the like). The reaction is carried out in the temperature range of about 50 to about 120 0 C and takes up to about 24 hours to complete.
• n, W, Ri, R2, R 3 and R 4 are as defined for Formula I.
• Compounds of Formula I are prepared by reacting a compound of formula 5 with a compound of formula 11 in the presence of a suitable solvent (for example, dioxane, and the like), a suitable catalyst (for example, Pd 2 (dba) 3 , and the like), a suitable ligand (for example, phosphine ligands such as (tBU)3PHBF3, and the like), a suitable inorganic base (for example, Cesium carbonate, and the like) under a suitable protective atmosphere (for example, argon, and the like).
• a suitable solvent for example, dioxane, and the like
• a suitable catalyst for example, Pd 2 (dba) 3 , and the like
• a suitable ligand for example, phosphine ligands such as (tBU)3PHBF3, and the like
• a suitable inorganic base for example, Cesium carbonate,
• n, W, Ri, R 2 , R 3 and R 4 are as defined for Formula I.
• Compounds of Formula I are prepared by reacting a compound of formula 5 with a compound of formula 12 in the presence of a suitable solvent (for example, THF, and the like), a suitable reagent (for example, triphosgene, CDI, and the like) and a suitable base (for example, triethylamine, and the like). The reaction is carried out in the temperature range of about 0 to about 5O 0 C and takes up to about 6 hours to complete.
• a suitable solvent for example, THF, and the like
• a suitable reagent for example, triphosgene, CDI, and the like
• a suitable base for example, triethylamine, and the like
• a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
• a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
• the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
• the free acid or free base forms of the compounds of the invention can be prepared from. the corresponding base addition salt or acid addition salt from, respectively.
• a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and. the like).
• a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
• Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
• a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
• a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
• Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
• appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
• Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
• solvates e.g., hydrates
• Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
• Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). 'Diastereomers have' distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
• the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
• the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
• a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet,
• the compounds of Formula I can be made by a process, which involves:
• Step A 6-Hydroxyisoquinoline (1.0 g, 6.9 mmol) and methyl 2- bromoisobutyrate (3.4 mL, 27.5 mmol) are dissolved in dry DMF (20 mL). Powdered potassium carbonate (3.8 g, 27.5 mmol) is added and the mixture is heated at 100 °C for 16 h. The mixture is cooled, diluted- with ethyl acetate (40 mL), washed with water (3 x 50 mL) and brine (50 mL).
• Step B Methyl 2-(isoquinolin-6-yloxy)-2-methylpropanoate 1 (1.1 g, 4.5 mmol) is dissolved in glacial acetic acid (20 mL). Pt ⁇ 2( ⁇ 50 mg, cat) is added, then the vessel is pressurized with H ⁇ to 55 psi and evacuated 3 times, then pressurized to 55 psi and shaken at r.t. for 16 h. The mixture is filtered through celite, then evaporated to dryness, dissolved in dichloromethane and evaporated to give the title compound 2 (0.99 g, 89%) as a yellow oil. 1 H-NMR (400 MHz 5 .
• Step A Methyl 2-(isoquinolin-6-yloxy)-2-methylpropanoate 1 (55 mg,
• Step B Methyl 2-(5-bromoisoquinolin-6-yloxy)-2-methylpropanoate 5
• Step C Methyl 2-(5-methylisoquinolin-6-yloxy)-2-methylpropanoate 6
• Step A 3,4-dihydro-6-methoxyisoquinolin-l(2H)-one (760 mg, 4.3 mmol) is dissolved in 48% aqueous HBr (5 mL) and heated at 100 0 C for 72 h. The mixture is cooled and poured into a saturated solution of NaHCU3 (50 mL) and extracted with ethyl acetate (2 x 20 mL). The organic fractions are combined, washed with brine (20 mL), dried (MgSO 4 ), filtered and evaporated to give crude 3,4-dihydro-6-hydroxyisoquinolin- l(2H)-one 8 (193 mg, 27%), which is used in Step B without further purification.
• Step B 3,4-dihydro-6-hydroxyisoquinolin-l(2H)-one 8 (193 mg, 1.2 mmol) and methyl 2-bromoisoburyrate (0.60 mL, 4.7 mmol) is dissolved in anhydrous DMF (10 mL). Powdered potassium carbonate (0.65 g, 4.7 mmol) is added and the mixture is heated at 100 0 G for 16 h.- The mixture is cooled, diluted with ethyl acetate (20 mL), washed with water (3 x 20 mL) and brine (20 mL). The organic layer is dried (MgSO 4 ), filtered, and evaporated to provide the title compound 9. MS calcd. for Cf 4 Hi 8 NO 4 (M+H + ) 264.1, found 264.1.
• Step A 2-bromo-l-(4-(trifluoromethyl)phenyl)ethanone (17 g, 63 mmol) and ethyl thiooxamate (8.4 g, 63 mmol) are heated at reflux in EtOH (20 mL) for 2 h.
• Step B Ethyl 4-(4-(trifluoromethyl)phenyl)thiazole-2-carboxylate 12 (5.0 g, 16.6 mmol) is dissolved in dry THF (35 mL) and cooled to 0 °C. LiAlH 4 (25 mL of 1.0 N in THF) is added dropwise to the solution and stirred at 0 0 C for 1 h. The reaction is quenched with dropwise addition of 1 N HCl (50 mL), and extracted into ethyl acetate (50 mL).
• Step C (4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methanol 13 (1.68 g,
• Step A 2-bromo-l-(4-(trifluoromethyl)phenyl)ethanone (5.3 g, 20 mmol) and 2-cyanothioacetamide (2.0 g, 20 mmol) are heated at reflux in EtOH (20 mL) for 2 h. The solvent is evaporated to provide crude-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)acetonitrile 16 which is used in Step B without further purification. MS calcd. for C12H8F3N2S (M+H+) 269.0, found 269.0.
• Step B 2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)acetonitrile 16 (20 mmol) is dissolved in a mixture of methoxyethanol (100 mL) and water (20 mL). Potassium hydroxide (6.7 g, 120 mmol) is added and the mixture is heated at 100 °C for 16 h. The mixture is acidified with 1 N HCl to pH 1 and extracted with ethyl acetate (2 x 200 mL).
• Step A 2-bromo-l-(4-(trifluoromethyl)phenyl)ethanone (2.0 g, 7.5 mmol) and NaSCN (728 mg, 9.0 mmol) are heated at reflux in EtOH (10 mL) for 2 h. The mixture is acidified with 1 N HCl (10 mL), extracted with ethyl acetate (20 mL), washed with brine (10 mL), dried (MgSO4), filtered and evaporated to provide crude l-(4- (trifluoromethyl)phenyl)-2-thiocyanatoethanone .18 which is used in Step B without further purification. MS calcd. for C10H7F3NOS (M+H+) 246.0, found 246.0.
• Step B l-(4-(trifluoromethyl)phenyl)-2-thiocyanatoethanone 18 (7.4 mmol) is dissolved in a mixture of THF (5 mL) and 4.0 N HCl in dioxane (5 mL) and heated at reflux for 16 h.
• Step A To the solution of ethyl ethynyl ether (6.0 g, 85.6 mmol) in THF
• Step B l-(2-ethoxy-vinyl)-4-trifluoromethyl-benzene 20 (9.24 g, 42.74 mmol) is dissolved in the solution of EtOH (200 mL), then NBS (7.61 g, 42.74 mmol) is added and stirred at rt for 2 hs. The mixture is concentrated to give crude product, which is purified by silic gel chromatography by EtOAc/hexane to give l-(l-bromo-2,2-diethoxy- ethyl)-4-trifluoromethyl-benzene 21 (12.87 g, 88.2 %) as a colorless oil.
• Step C l-(l-Bromo-2,2-diethoxy-ethylj-4-trifluoromethyl-benzene 21
• Step D The aldehyde 22 (100 mg, 0.375 mmol) is dissolved in EtOH (1.0 mL), then thioacetamide (28.13 mg, 0.375 mmol) is added and the mixture is stirred at 9O 0 C for 15 hs. The solution is diluted EtOAc (50 mL) and washed with saturated NaHCO 3 (30 mL) and brine (10 mL).
• Step E 2-methyl-5-(4-trifluoromethyl-phenyl)-thiazole 23 (1.3 g, 5.3 mmol) and N-bromosuccinimide (1.24 g, 6.9 mmol) are suspended in carbon tetrachloride (100 mL) and heated to 40 "C. 2,2-azo-bis-isobutyronitrile (AIBN 5 88 mg, 0.53 mmol) is added and the mixture is heated to 70 °C for 12 h.
• AIBN 5 88 mg, 0.53 mmol 2,2-azo-bis-isobutyronitrile
• Step A The amine 2 (40 mg, 0.16 mmol), the chloride 14 (45 mg, 0.16 mmol) and diisopropylethylamine (79 ⁇ L, 0.48 mmol) are dissolved in 1,2-dichloroethane (3 mL) and heated to 80 0 C for "16 h.” The solvent is removed in vacuo to give crude methyl 2-(2-((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)-l s 2,3,4- tetrahydroisoquinolin-6-yloxy)-2-methylpropanoate 25, which is used in Step B without further purification. MS calculated for C 25 H 26 F 3 N 2 O 3 S (M+H*) 491.2, found 491.1.
• Step B The residue from Step A is dissolved in THF (3 mL) and 1 N LiOH
• Step A 4-(4-(Trifluoromethyl)phenyl)thiazole-2-carboxylic acid 15 (55 mg, 0.20 mmol) is dissolved in THF (4 mL) and cooled to 0 °C.
• Diisopropylethylamine (73 ⁇ L, 0.44 mmol) and l : [3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI, 42 mg, 0.22 mmol) are added and stirred at 0 °C for 5 min, then 1-hydroxybenzotriazole hydrate (HOBT 5 34 mg, 0.22 mmol) is added and stirred a further 30 min.
• HOBT 5 34 mg, 0.22 mmol 1-hydroxybenzotriazole hydrate
• Step B The residue from Step A is dissolved in THF (3 mL) and 1 N LiOH
• Step A Methyl 2-(l,2,3,4-tetrahydroisoquinolin-6-yloxy)-2-
• Step B THF (1 mL) and 1 N LiOH (0.5 mL) are added directly to the reaction mixture from Step A and stirred at rt for 3 h. The mixture is then acidified with 1 N HCl ( ⁇ 5 mL) and extracted with EtOAc (1.0.
• Step A 4-(4-(trifluoromethyl)phenyl)thiazol-2-amine 11 (58 mg, 0.24 mmol) is dissolved in anhydrous THF (5 mL) and triethylamine (100 ⁇ L, 0.72 mmol) and cooled to 0 0 C.
• Triphosgene (24 mg, 0.08 mmol) is added and stirred at 0 °C for 5 min, then methyl 2-(l,2,3,4-tetrahydroisoquinolin-6-yloxy)-2-methylpropanoate 2 (60 mg, 0.24 mmol) is added and the mixture is stirred at rt for 3 h.
• Step B (for D2 only) Methyl 2-(2-(4-(4-(trifluoromethyl)phenyl)thiazol-2- ylcarbamoyl)-l,2,3,4-tetrahydroisoquinolin-6-yloxy)-2-methylpropanoate 28 (20 mg, 0.038 mmol) is dissolved in dry acetonitrile (5 mL). Powdered cesium carbonate (44 mg, 0.13 mmol) and iodomethane (8 ⁇ L, 0.11 mmol) are added and the mixture is stirred at rt for 2 h.
• Step C Intermediate 28 (Dl) or 29 (D2) is dissolved in THF (3 mL) then 1
• Transfection assays are used to assess the ability of compounds of the invention to modulate the transcriptional activity of the PPARs. Briefly, expression vectors for chimeric proteins containing the DNA binding domain of yeast GAL4 fused to the ligand-binding domain (LBD) of either PPAR ⁇ , PP ARa or PPAR ⁇ are introduced via transient transfection into mammalian cells, together with a reporter plasmid where the luciferase gene is under the control of a GAL4 binding site. Upon exposure to a PPAR modulator, PPAR transcriptional activity varies, and this can be monitored by changes in luciferase levels. If transfected cells are exposed to a PPAR agonist, PPAR-dependent transcriptional activity increases and luciferase levels rise.
• LBD ligand-binding domain
• Penicillin/Streptomycin/Fungizome DMEM Media.
• the cells are harvested by washing with PBS (30ml) and then dissociating using trypsin (0.05%; 3ml).
• the trypsin is inactivated by the addition of assay media (DMEM, CA-dextran fetal bovine serum (5%).
• DMEM assay media
• the cells are spun down and resuspended to 170,000cells/ml.
• a Transfection mixture of GAL4-PPAR LBD expression plasmid (l ⁇ g), UAS-luciferase reporter plasmid (l ⁇ g), Fugene (3:1 ratio; 6 ⁇ L) and serum-free media (200 ⁇ L) was prepared and incubated for 15-40 minutes at room temperature.
• Transfection mixtures are added to the cells to give 0.16M cells/mL, and cells (50 ⁇ l/well) are then plated into 384 white, solid-bottom, TC- treated plates. The cells are further incubated at 37 0 C, 5.0% CO 2 for 5-7 hours. A 12- point series of dilutions (3 fold serial dilutions) are prepared for each test compound in DMSO with a starting compound concentration of lO ⁇ M. Test compound (50OnI) is added to each well of cells in the assay plate and the cells are incubated at 37°C, 5.0% CO 2 for 18-24 hours. The cell lysis/luciferase assay buffer, Bright-GloTM (25%; 25 ⁇ l; Promega), is added to each well. After a further incubation for 5 minutes at room temperature, the luciferase activity is measured.
• Raw luminescence values are normalized by dividing them by the value of the DMSO control present on each plate. Normalized data is analyzed and dose-response curves are fitted using Prizm graph fitting program. EC50 is defined as the concentration at which the compound elicits a response that is halfway between the maximum and minimum values. Relative efficacy (or percent efficacy) is calculated by comparison of the response elicited by the compound with the maximum value obtained for a reference PPAR modulator.
• Compounds of Formula I,'in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application.
• Compounds of the invention preferably have an EC50 for PPAR ⁇ and/or PP ARa and/or PPAR ⁇ , of less than 5 ⁇ M, mo ⁇ e preferably less than l ⁇ M, more preferably less than 500nm, more preferably less than 10OnM.
• Compounds of the invention preferably have an EC50 for PPAR ⁇ that is less than or equal to PPAR ⁇ which in turn has an EC50 that is at least 10-fold less than PPAR ⁇ .

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